title: Synthesis and chemical and biological comparison of nitroxyl- and nitric oxide-releasing diazeniumdiolate-based aspirin derivatives.
abstract: Structural modifications of nonsteroidal anti-inflammatory drugs (NSAIDs) have successfully reduced the side effect of gastrointestinal ulceration without affecting anti-inflammatory activity, but they may increase the risk of myocardial infarction with chronic use. The fact that nitroxyl (HNO) reduces platelet aggregation, preconditions against myocardial infarction, and enhances contractility led us to synthesize a diazeniumdiolate-based HNO-releasing aspirin and to compare it to an NO-releasing analogue. Here, the decomposition mechanisms are described for these compounds. In addition to protection against stomach ulceration, these prodrugs exhibited significantly enhanced cytotoxcity compared to either aspirin or the parent diazeniumdiolate toward nonsmall cell lung carcinoma cells (A549), but they were not appreciably toxic toward endothelial cells (HUVECs). The HNO-NSAID prodrug inhibited cylcooxgenase-2 and glyceraldehyde 3-phosphate dehydrogenase activity and triggered significant sarcomere shortening on murine ventricular myocytes compared to control. Together, these anti-inflammatory, antineoplasic, and contractile properties suggest the potential of HNO-NSAIDs in the treatment of inflammation, cancer, or heart failure.
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Debashree
authors.initials: D
authors.lastname: Basudhar
authors.forename: Gaurav
authors.initials: G
authors.lastname: Bharadwaj
authors.forename: Robert Y
authors.initials: RY
authors.lastname: Cheng
authors.forename: Sarthak
authors.initials: S
authors.lastname: Jain
authors.forename: Sa
authors.initials: S
authors.lastname: Shi
authors.forename: Julie L
authors.initials: JL
authors.lastname: Heinecke
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Holland
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Ridnour
authors.forename: Viviane M
authors.initials: VM
authors.lastname: Caceres
authors.forename: Regina C
authors.initials: RC
authors.lastname: Spadari-Bratfisch
authors.forename: Nazareno
authors.initials: N
authors.lastname: Paolocci
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Velázquez-Martínez
authors.forename: David A
authors.initials: DA
authors.lastname: Wink
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Miranda
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001241:Aspirin / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001391:Azo Compounds / Q000737:chemistry*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+) / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008956:Models, Chemical; D015394:Molecular Structure; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000737:chemistry*; D009589:Nitrogen Oxides / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012518:Sarcomeres / Q000187:drug effects / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001391:Azo Compounds; D004791:Enzyme Inhibitors; D009589:Nitrogen Oxides; D011355:Prodrugs; C452539:diazeniumdiolate; D009569:Nitric Oxide; D051546:Cyclooxygenase 2; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+); C039900:nitroxyl; D001241:Aspirin